Congressional language has recently specified high priority "benchmarks" for epilepsy research, the first of which is identification of a surrogate marker for epileptogenicity. Our current research, and the investigations proposed here, focus on the identification and characterization of one of the first putative surrogate markers for epileptogenicity, an interictal electrophysiological epileptiform event termed "fast ripples" (FR). We have used in vivo microelectrode recordings to describe interictal FR and other high frequency oscillations in the hippocampus and entorhinal cortex of patients with mesial temporal lobe epilepsy (MTLE) and hippocampal sclerosis (HS) and in the intrahippocampal kainic acid (KA) rat model of this disorder. We have described the field potential and unit correlates of interictal FR, demonstrated that these interictal events occur preferentially in areas capable of generating spontaneous seizures, particularly those associated with HS, localized FR generation to small neuronal clusters in hippocampus and entorhinal cortex, and begun to show that their pathophysiological substrates are the same as those responsible for the generation of spontaneous hippocampal seizures in MTLE with HS. We now propose to extend these studies to determine the anatomical and electrophysiological characteristics of FR during the transition to hypersynchronous seizures which do not propagate and low voltage fast seizures which do and to localize neuronal elements activated in induction of these events. These studies at the systems level complement investigations into fundamental mechanisms of FR at the cellular and molecular levels, being carried out with our program project grant (NS02808). In addition, we propose to carry out genomic screening in the KA rat using DNA microarray technology, to distinguish patterns of gene expression change specific to areas generating interictal FR that could underlie epileptogenicity from nonepileptogenic patterns of gene expression change that result from lesion and epileptic activity. We will also use in situ hybridization to identify the cells exhibiting these gene expression changes. The long-term goal of this research direction is not only to gain insights that will elucidate fundamental mechanisms of epileptogenicity, ictal onset and propagation, but also ultimately to identify one or more surrogate markers of epileptogenicity which can be used to screen potential antiepileptic and antiepileptogenic compounds, identify the boundaries of the epileptogenic region for resective surgery, adjust antiepileptic drug treatment in individual patients, and perhaps predict which patients will develop epilepsy after cerebral insults.